Prostate cancer is diagnosed in almost 200,000 men every year in the US and accounts for about 38,000 annual deaths. In this application, we intend to take a molecular epidemiologic approach to examining our central hypothesis that risk of prostate cancer is substantially influenced by specific genotypes in the human 5alpha-reductase type II (SRD5A2) gene. We propose to investigate the following seven specific aims with molecular genetic and epidemiologic tools: 1) To determine the relationship between the SRD5A2 gene and prostate cancer by genotyping a particular polymorphic DNA marker [TA short tandem repeat (TA-STR)] in the SRD5A2 gene in men with prostate cancer and matched controls from African-American and White men at widely different risks of prostate cancer. 2) To characterize DNA sequence variations in the SRD5A2 gene that predispose men to prostate cancer by sequencing DNA from a small number of African-American and White men with prostate cancer, who carry the high risk SRD5A2 genotypes identified in (1), and so to determine the precise nature of the germline DNA alterations predisposing to prostate cancer. 3) To characterize DNA sequence variations in the SRD5A2 gene that may protect Asian men from prostate cancer by sequencing DNA from a small number of normal (control) Asian men who have low levels of dihydrotestosterone (DHT), and so to determine the germline DNA alterations which may be protective against prostate cancer. 4) To determine the biochemical properties (enzyme activity) of each sequence variation identified in (2) and (3). This will distinguish irrelevant polymorphisms from actual activity altering mutations. 5) To determine the relationship between the SRD5A2 gene and prostate cancer by genotyping [using the relevant sequence variations identified in (4)] the SRD5A2 gene in three racial-ethnic groups [Asian- Americans (defined here as Chinese- and Japanese-Americans), African- Americans and Whites] of prostate cancer cases and matched controls. 6) To utilize the results on the strength of the associations identified in (5) and the prevalence of these alleles in the three racial-ethnic groups, to estimate the contribution of SRD5A2 genotype in explaining the variation in prostate cancer risk among these three groups of men at widely differing risk of prostate cancer. 7) To further characterize the involvement of the SRD5A2 gene in prostate cancer by defining somatic mutations in this gene.